Experimental autoimmune thyroiditis in mice serves as a prototype for the study of human chronic thyroiditis as well as other organ-specific autoimmune disorders. The autoimmune response to thyroglobulin, the major thyroid antigen, is under genetic control. Previous studies have identified a primary immunoregulatory gene (Ir-Tg) at the I-A subregion of H-2, and a modifying gene at the D end. The present proposal is aimed at using T cell subsets and clones specific for various antigenic determinants of mouse thyroglobulin (MTg) to investigate the mechanisms of action of the major Ir-Tg gene in regulating the production of autoantibodies and thyroid lesions. We have also examined the effector mechanisms of thyroid damage using a recently developed cell-mediated cytotoxicity assay on functional thyroid monolayer cultures. The effector cells will be characterized. The role of modifying D-end gene(s) in both antigen recognition and cytotoxicity will be studied.